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Item does not contain fulltext OBJECTIVE: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. METHODS: Using a novel deep learning framework trained to predict biological sex based on T(1)-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T(1)-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). RESULTS: Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. CONCLUSIONS: The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

Neuroimaging analyses of brain structure and function in autism have typically been conducted in isolation, missing the sensitivity gains of linking data across modalities. Here we focus on the integration of structural and functional organisational properties of brain regions. We aim to identify novel brain-organisation phenotypes of autism. We utilised multimodal MRI (T1-, diffusion-weighted and resting state functional), behavioural and clinical data from the EU AIMS Longitudinal European Autism Project (LEAP) from autistic (n = 206) and non-autistic (n = 196) participants. Of these, 97 had data from 2 timepoints resulting in a total scan number of 466. Grey matter density maps, probabilistic tractography connectivity matrices and connectopic maps were extracted from respective MRI modalities and were then integrated with Linked Independent Component Analysis. Linear mixed-effects models were used to evaluate the relationship between components and group while accounting for covariates and non-independence of participants with longitudinal data. Additional models were run to investigate associations with dimensional measures of behaviour. We identified one component that differed significantly between groups (coefficient = 0.33, padj = 0.02). This was driven (99%) by variance of the right fusiform gyrus connectopic map 2. While there were multiple nominal associations with behavioural measures, none were significant following multiple comparison correction. Our analysis considered the relative contributions of both structural and functional brain phenotypes simultaneously, finding that functional phenotypes drive associations with autism. These findings expanded on previous unimodal studies by revealing the topographic organisation of functional connectivity patterns specific to autism and warrant further investigation.

Contains fulltext : 248865.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

Contains fulltext : 248888.pdf (Publisher’s version ) (Open Access) BACKGROUND: Poor working memory, lower IQ and maladaptive behaviour form a triple disability known to have negative effects on the academic and social development of children with borderline intellectual functioning (BIF; IQ: 70

Contains fulltext : 282515.pdf (Publisher’s version ) (Open Access) Schizophrenia is a severely debilitating neurodevelopmental disorder that requires continuous multidisciplinary treatment. Early onset schizophrenia (EOS, onset before 18) is associated with poorer outcomes than the adult-onset type. The transition from adolescent to adult mental healthcare services (AMHS) poses various challenges for maintaining continuity of care. The heterogeneous availability of specialized mental health services and resources for people with schizophrenia across Europe and the inadequacy of training programs in creating a shared culture and knowledge base between child and adult mental health professionals are major challenges at the policy level. More flexible and individualized transition timing is also needed. While changes in the relationship between patients, caregivers and mental health professionals at a time when young people should acquire full responsibility for their own care are challenges common to all mental health disorders, these are particularly relevant to the care of schizophrenia because of the severe associated disability. This Expert Opinion Paper examines the main aspects of transitioning of care in schizophrenia with the aim of identifying the challenges and the potential approaches that could enhance continuity of care.

Although aggression has been linked to disturbances of circadian rhythm, insight into the neural substrate of this association is currently lacking. The suprachiasmatic nucleus (SCN) of the hypothalamus, the master circadian clock, is regulated by clock genes and known to influence the secretion of cortisosterone and testosterone, important hormones implicated in aggression. Here, we investigated deviations in the regulation of the locomotor circadian rhythm and hormonal levels in a mouse model of abnormal aggression. We tested aggressive BALB/cJ and control BALB/cByJ mice in the resident-intruder paradigm and compared them on their locomotor circadian rhythm during a 12 h light/12 h dark cycle and constant darkness. State (serum) corticosterone and trait (hair) corticosterone and testosterone levels were determined, and immunohistochemistry was performed to assess the expression of important clock proteins, PER1 and PER2, in the core and shell of the SCN at the start of their active phase. Compared with BALB/cByJ mice, aggressive BALB/cJ mice displayed: (1) a shorter free-running period in constant darkness; (2) reduced state corticosterone variability between circadian peak and trough but no differences in corticosterone trait levels; (3) lower testosterone trait levels; (4) higher PER1 expression in the SCN shell with no changes in PER2 in either SCN subregion during the early dark phase. Together, these results suggest that aggressive BALB/cJ mice have disturbances in different components encompassing the circadian and hormonal cycle, emphasizing their value for future investigation of the causal relationship between SCN function, circadian clocks and aggression.

Contains fulltext : 248384.pdf (Publisher’s version ) (Open Access) Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e- diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and con- trols aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within- subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive ( n = 48), 2. in- dividuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls ( n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072) = 5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Indi- viduals with a combined presentation significantly showed the steepest slope of physical ac- tivity on positive affect (slope_inattentive = 0.005, p < 0.001; slope_combined = 0.009, p < 0.001; slope_controls = 0.004, p = 0.008). Our analyses on negative affect revealed a negative associ- ation only in the individuals with a combined presentation (slope = -0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mech- anism reinforcing hyperactivity needs to be empirically clarified in future studies., European Commission 667302, ECNP Network

Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA‐Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population‐level mapping of average asymmetry was achieved, including an intriguing fronto‐occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi‐dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive–compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders., Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Over the last four years, the ENIGMA‐Laterality Working Group has published six studies of grey matter morphological asymmetry in health and disease, based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. Here we review the findings from these six studies.

Contains fulltext : 287522.pdf (Publisher’s version ) (Open Access) Impaired emotion recognition is common in individuals with attention-deficit/hyperactivity disorder (ADHD) and may, via deficient emotion self-regulation, relate to the frequently co-occurring affective and social problems. The present study used an emotional face-matching task and functional magnetic resonance imaging (fMRI) to investigate neural responses during the processing of angry and fearful faces and visuo-spatial control stimuli. Additionally, measures for emotion dysregulation, ADHD type, and age were investigated in relation to the behavioral and neural fMRI data. We utilized a sample of 61 adolescents/young adults with ADHD and 51 age-matched healthy controls (age range: 12-28 years). Participants with ADHD had higher emotion dysregulation scores than controls. They also reacted slower and less accurate in response to emotional but not visuo-spatial control stimuli. Neural response differences between emotional and visuo-spatial trials were significantly smaller in cases, particularly in the left amygdala. While coupling between the right amygdala and bilateral ventromedial prefrontal cortex was stronger for emotional than visuo-spatial stimuli in control subjects, levels of positive coupling between the trial types did not significantly differ in participants with ADHD. Neither emotion dysregulation scores, nor ADHD type or age were related to the behavioral and neural processing alterations during the emotional face-matching task. Results indicate that emotion recognition deficits in ADHD are particularly associated with lower amygdala activation to emotional stimuli and alterations in the functional connections of the amygdala to medial prefrontal areas. Emotion recognition deficits and associated neural alterations were unrelated to emotion dysregulation, ADHD type, or age.

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

Contains fulltext : 293775.pdf (Publisher’s version ) (Open Access) BACKGROUND: Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent. METHODS: The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. RESULTS: Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. CONCLUSIONS: The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.

Despite a general decrease of attention-deficit/hyperactivity disorder (ADHD) symptoms during adolescence, these may persist in some individuals but not in others. Prior cross-sectional studies have shown that parenting style and their interaction with candidate genes are associated with ADHD symptoms. However, there is a lack of longitudinal research examining the independent and interactive effects of parenting and plasticity genes in predicting the course of attention-deficit/hyperactivity disorder (ADHD) symptoms across adolescence. Here, we investigated how children perceived their parents’ parenting style (i.e., rejection, overprotection, and emotional warmth) at the age of 11, and their interaction with DRD4,MAOA, and 5-HTTLPR genotypes on parent-reported ADHD symptoms at three time points (mean ages 11.1, 13.4, and 16.2 years) in 1730 adolescents from the TRacking Adolescents’ Individual Lives Survey (TRAILS). Growth Mixture Modeling in Mplus identified four ADHD symptom trajectories: low, moderate stable, high decreasing, and high persistent. Perceived parental rejection predicted class membership in the high persistent trajectory compared to the other classes (p

BackgroundAlthough the importance of early detection and early intervention of autism spectrum disorders (ASD) is widely recognized, multiple barriers exist in accessing early intervention services. As an alternative to these barriers, the SCOPE project presents a new, easy accessible and blended intervention called BEAR (Blended E-health for children at eArly Risk). This paper describes this BEAR intervention and study design of an ongoing two arm cluster randomized controlled trial (RCT).MethodsBEAR (Blended E-health for children at eArly Risk) is a blended e-health intervention, based on evidence-based naturalistic developmental behavioral interventions (NDBI’s) and can be offered to parents and infants/toddlers at high likelihood for ASD. During the ongoing RCT,N = 88 high risk infants and toddlers will be cluster randomized over the BEAR intervention and care-as-usual (CAU) conditions. The finalized version of the intervention protocol and study design are presented in this paper. The primary outcome measure isjoint engagementmeasured by the Joint Engagement Rating Inventory (JERI) during videotaped parent–child interaction. Secondary outcome measures include severity of ASD symptoms, global level of adaptive functioning, parental well-being, parental skills and satisfaction with healthcare. Also, costs will be estimated from society's perspective. Assessments take place at the start of the study (T1), after eight weeks (T2) and after six months (T3) and include behavioral home observations and parental questionnaires.DiscussionThe SCOPE project aims to contribute to improved early identification and timely start of suitable interventions for infants and toddlers at elevated likelihood for ASD. This ongoing RCT will offer insight in the feasibility, short-term and six months effects of the innovative BEAR intervention. It is estimated that inclusion for the trial (N = 88) is completed in spring 2023.Trial registrationDutch Trial Register, NTR7695. Registered at December 17th, 2018,www.trialregister.nl.

Aims: Between 2008 and 2012, the number of children and adolescents in the Netherlands who received methylphenidate prescriptions increased by 35.6%. We determined guideline adherence regarding the assessment of attention-deficit/hyperactivity disorder (ADHD) and rates of off-label use in those 2 years. We also compared adherence to guidelines between mental health and pediatrics settings. Methods: We conducted a medical file audit of 506 children or adolescents who had received a first methylphenidate prescription in 2008 (n = 208) or 2012 (n = 298) across mental health (n = 333) and pediatrics outpatient clinics (n = 173) in the Netherlands and assessed adherence to seven guideline recommendations. Results: We did not find significant differences between 2008 and 2012 regarding the mean adherence to the seven recommendations (43% vs. 45%) or the percentage of off-label use (35% vs. 30%). Best adherence rates (over the years 2008 and 2012 combined) concerned the assessment of comorbidities (89%) and the involvement of teachers in the diagnostic process (75%). Least frequently adhered to were assessing ADHD severity (1%), the use of a (semi-)structured parent interview (16%), and providing psycho-education to parents (42%) or teachers (1%). Mental health settings showed better adherence than pediatrics settings (over the years 2008 and 2012 combined) concerning the use of (semi-)structured parent interviews (22% vs. 3.1%), having a separate diagnostic session directed at the child (81% vs. 63%), assessment of comorbidities (95% vs. 76%), and providing psycho-education to parents (51% vs. 24%). Conclusions: There was neither a decrease in adherence to guidelines nor an increase in off-label use between 2008 and 2012. However, there is ample room for improvement regarding guideline adherence.

Background Difficulties in social communication are a defining clinical feature of autism. However, the underlying neurobiological heterogeneity has impeded targeted therapies and requires new approaches to identifying clinically relevant bio-behavioural subgroups. In the largest autism cohort to date, we comprehensively examined difficulties in facial expression recognition, a key process in social communication, as a bio-behavioural stratification biomarker, and validated them against clinical features and neurofunctional responses. Methods Between 255 and 488 participants aged 6–30 years with autism, typical development and/or mild intellectual disability completed the Karolinska Directed Emotional Faces task, the Reading the Mind in the Eyes Task and/or the Films Expression Task. We first examined mean-group differences on each test. Then, we used a novel intersection approach that compares two centroid and connectivity-based clustering methods to derive subgroups based on the combined performance across the three tasks. Measures and subgroups were then related to clinical features and neurofunctional differences measured using fMRI during a fearful face-matching task. Results We found significant mean-group differences on each expression recognition test. However, cluster analyses showed that these were driven by a low-performing autistic subgroup (~ 30% of autistic individuals who performed below 2SDs of the neurotypical mean on at least one test), while a larger subgroup (~ 70%) performed within 1SD on at least 2 tests. The low-performing subgroup also had on average significantly more social communication difficulties and lower activation in the amygdala and fusiform gyrus than the high-performing subgroup. Limitations Findings of autism expression recognition subgroups and their characteristics require independent replication. This is currently not possible, as there is no other existing dataset that includes all relevant measures. However, we demonstrated high internal robustness (91.6%) of findings between two clustering methods with fundamentally different assumptions, which is a critical pre-condition for independent replication. Conclusions We identified a subgroup of autistic individuals with expression recognition difficulties and showed that this related to clinical and neurobiological characteristics. If replicated, expression recognition may serve as bio-behavioural stratification biomarker and aid in the development of targeted interventions for a subgroup of autistic individuals.

Contains fulltext : 248366.pdf (Publisher’s version ) (Open Access) Structural brain alterations in autism spectrum disorder (ASD) are heterogeneous, with limited effect sizes overall. In this study, we aimed to identify subgroups in ASD, based on neuroanatomical profiles; we hypothesized that the effect sizes for case/control differences would be increased in the newly defined subgroups. Analyzing a large data set from the ENIGMA-ASD working group (n = 2661), we applied exploratory factor analysis (EFA) to seven subcortical volumes of individuals with and without ASD to uncover the underlying organization of subcortical structures. Based on earlier findings and data availability, we focused on three age groups: boys ( = 22 years). The resulting factor scores were used in a community detection (CD) analysis to cluster participants into subgroups. Three factors were found in each subsample; the factor structure in adult men differed from that in boys and male adolescents. From these factors, CD uncovered four distinct communities in boys and three communities in adolescents and adult men, irrespective of ASD diagnosis. The effect sizes for case/control comparisons were more pronounced than in the combined sample, for some communities. A significant group difference in ADOS scores between communities was observed in boys and male adolescents with ASD. We succeeded in stratifying participants into more homogeneous subgroups based on subcortical brain volumes. This stratification enhanced our ability to observe case/control differences in subcortical brain volumes in ASD, and may help to explain the heterogeneity of previous findings in ASD. LAY SUMMARY: Structural brain alterations in ASD are heterogeneous, with overall limited effect sizes. Here we aimed to identify subgroups in ASD based on neuroimaging measures. We tested whether the effect sizes for case/control differences would be increased in the newly defined subgroups. Based on neuroanatomical profiles, we succeeded in stratifying our participants into more homogeneous subgroups. The effect sizes of case/control differences were more pronounced in some subgroups than those in the whole sample.

Item does not contain fulltext 01 januari 2023

Network modeling of the social, communication and restrictive/repetitive behaviors (RRBs) included in the definition of Autism Spectrum Disorder was performed. The Autism Diagnostic Interview-Revised (ADI-R) assessed behaviors in 139 pre-school cases at two cross-sections that averaged 34.8 months apart. Cross-sectional networks were based on the correlation matrix of the ADI-R behavioral items and the "bootCross" method was developed and enabled the estimation of a longitudinal network. At both stages, RRB items/nodes formed a consistent peripheral cluster, while social and communication nodes formed a core cluster that diverged with time. These differences in the nature and evolution of the RRB and socio-communicative dimensions indicate that their inter-behavior dynamics are very different. The most central behaviors across stages are proposed as prime targets for efficient therapeutic intervention.

Contains fulltext : 248841.pdf (Publisher’s version ) (Open Access) BACKGROUND: Family mindfulness-based intervention (MBI) for child attention-deficit/hyperactivity disorder (ADHD) targets child self-control, parenting and parental mental health, but its effectiveness is still unclear. METHODS: MindChamp is a pre-registered randomised controlled trial comparing an 8-week family MBI (called 'MYmind') in addition to care-as-usual (CAU) (n = 55) with CAU-only (n = 48). Children aged 8-16 years with remaining ADHD symptoms after CAU were enrolled together with a parent. Primary outcome was post-treatment parent-rated child self-control deficits (BRIEF); post hoc, Reliable Change Indexes were explored. Secondary child outcomes included ADHD symptoms (parent/teacher-rated Conners' and SWAN; teacher-rated BRIEF), other psychological symptoms (parent/teacher-rated), well-being (parent-rated) and mindfulness (self-rated). Secondary parent outcomes included self-ratings of ADHD symptoms, other psychological symptoms, well-being, self-compassion and mindful parenting. Assessments were conducted at post-treatment, 2- and 6-month follow-up. RESULTS: Relative to CAU-only, MBI+CAU resulted in a small, statistically non-significant post-treatment improvement on the BRIEF (intention-to-treat: d = 0.27, p = .18; per protocol: d = 0.33, p = .11). Significantly more children showed reliable post-treatment improvement following MBI+CAU versus CAU-only (32% versus 11%, p

BACKGROUND: Methylphenidate may improve executive functioning in children with attention-deficit/hyperactivity disorder (ADHD). However, it is unclear if there are still acute effects of methylphenidate on executive functioning after long-term use.METHODS: In a randomized double-blind, placebo-controlled discontinuation study, 94 children and adolescents (ages 8-18 years) who used methylphenidate beyond two years were either assigned to seven weeks of continued treatment with 36 or 54 mg of extended-release methylphenidate or to gradual withdrawal over three weeks to placebo for four weeks. Performance on neuropsychological tasks, measuring working memory, response inhibition, attentional flexibility and psychomotor speed was compared between both groups using mixed models for repeated measures. Additionally, we investigated within the discontinuation group if a deterioration on the investigator-rated Clinical Global Impressions Improvement scale after withdrawing to placebo was related to a worse performance on the neuropsychological tasks. This study was registered in the Netherlands Trial Register (www. Trialregister.nl) with identifier 5252.RESULTS: After withdrawal of methylphenidate, the discontinuation group made more errors on working memory (β = -1.62, SD = 0.56, t = -2.88, p = .01, Cohen's f2 = .14), independent from reaction time compared to baseline, in contrast to the continuation group. We did not find differences in changes in response inhibition, attentional flexibility and psychomotor speed between the two groups. Also, there were no significant differences in task measures between the participants who deteriorated clinically and those who did not.CONCLUSIONS: Our study shows that methylphenidate has a beneficial effect on working memory after two years of use. Future studies should explore whether cognitive outcomes may aid clinical decision-making on the continued use of methylphenidate, given dissociation between cognitive and behavioural effects of stimulant medication.

Autism spectrum disorder (autism) is a complex neurodevelopmental condition with pronounced behavioral, cognitive, and neural heterogeneities across individuals. Here, our goal was to characterize heterogeneity in autism by identifying patterns of neural diversity as reflected in BOLD fMRI in the way individuals with autism engage with a varied array of cognitive tasks.All analyses were based on the EU-AIMS/AIMS-2-TRIALS multisite Longitudinal European Autism Project (LEAP) with participants with autism (n = 282) and typically developing (TD) controls (n = 221) between 6 and 30 years of age. We employed a novel task potency approach which combines the unique aspects of both resting state fMRI and task-fMRI to quantify task-induced variations in the functional connectome. Normative modelling was used to map atypicality of features on an individual basis with respect to their distribution in neurotypical control participants. We applied robust out-of-sample canonical correlation analysis (CCA) to relate connectome data to behavioral data.Deviation from the normative ranges of global functional connectivity was greater for individuals with autism compared to TD in each fMRI task paradigm (all tasks p 0.001). The similarity across individuals of the deviation pattern was significantly increased in autistic relative to TD individuals (p 0.002). The CCA identified significant and robust brain-behavior covariation between functional connectivity atypicality and autism-related behavioral features.Individuals with autism engage with tasks in a globally atypical way, but the particular spatial pattern of this atypicality is nevertheless similar across tasks. Atypicalities in the tasks originate mostly from prefrontal cortex and default mode network regions, but also speech and auditory networks. We show how sophisticated modeling methods such as task potency and normative modeling can be used toward unravelling complex heterogeneous conditions like autism.

In the last two decades, there has been a growing body of research that identified sex-related differences in attention-deficit hyperactivity disorder (ADHD). Our objective was to quantify whether these sex differences are based on altered functional brain connectivity profiles. In addition, we investigated whether the presence of comorbid disorders, including depression, substance use disorder (SUD) and overweight, influenced these sex differences. A seed-based connectivity analysis of the external globus pallidus (GPe), an important inhibitory relay hub of the fronto-thalamo-striatal-loop, was performed. In a first step, we searched for sex-related differences in ADHD patients (

Contains fulltext : 282576.pdf (Publisher’s version ) (Open Access)

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that could persist into adulthood with known abnormalities in brain structure. Genetics also play an important role in the etiology of the disorder and could affect the disorder trajectory. In this study, we investigated the prediction power of brain image and genomic features for symptom change in 77 individuals with ADHD as part of NeuroIMAGE cohort. Gray matter components and working memory assessments at baseline, as well as gene scores of interest, were used to predict the changes in the two symptom domains: inattentive and hyperactive/impulsive, an average of 4 years. A linear regression model coupled with various feature selection approaches, including leave-one-out-cross-validation (LOOCV), stability selection with resampling, and permutation tests, was implemented to mitigate the overtraining potential caused by small sample sizes. Results showed that traditional LOOCV overestimated the prediction power. We proposed a novel stability selection with the threshold set by permutation tests, which provided more objective assessment. Using our proposed procedure, we identified a statistical promising prediction model for inattention symptom change; the consistent correlation between predicted values and measured values during model training, validating and hold out testing (r=0.64, 0.53, 0.46, respectively), but the p value is not significant in the holdout test. The selected features include age, gray matter in the insula, genes OSBPL1A, CTNNB1, PRPSAP2, ACADM, and polygenic risk score of education attainment, which have been previously reported to be associated with ADHD. We speculate that significant associations may be observed with a large sample size.

To improve early detection of autism spectrum disorder in preventive care, a Dutch guideline was developed 5 years ago. The guideline provides preventive care physicians at well-baby clinics action-oriented advice and describes a step-by-step approach for children identified at an increased risk for autism spectrum disorder during general healthcare surveillance. This qualitative study evaluated the guideline adherence and studied barriers regarding early detection of autism spectrum disorder at well-baby clinics. Semi-structured interviews were undertaken with 12 preventive care physicians (one representative per province). Interviews were analyzed using grounded theory. It was found that the vast majority of participants did not follow-up general surveillance with an autism spectrum disorder–specific screener as prescribed by the guideline. Six barriers, to be divided in personal, guideline-related and external factors, were found regarding early detection of autism spectrum disorder and adherence to the guideline. The results of this study highlight the importance of an integrative approach, raising awareness of the benefits regarding early detection of autism spectrum disorder in preventive care, the need of continuous investment in easy and accessible training and active screening, and a closer collaboration between preventive care organizations and autism spectrum disorder experts. Lay Abstract To improve early detection of autism spectrum disorder in preventive care, a Dutch guideline was developed 5 years ago. The guideline provides preventive care physicians at well-baby clinics action-oriented advice and describes a step-by-step approach for children identified at an increased risk for autism spectrum disorder during general healthcare surveillance. The present qualitative study evaluated adherence to the guideline and studied barriers regarding early detection of autism spectrum disorder at well-baby clinics. Interviews were undertaken with 12 preventive care physicians (one representative per province). It was found that the vast majority of participants did not follow-up general surveillance with an autism spectrum disorder -specific screener as prescribed by the guideline. Six barriers (limited knowledge about autism spectrum disorder symptoms in infant and toddlerhood, professional attitude toward early detection, problems in discussing initial worries with parents, limited use of screening instruments, perceptions toward cultural and language differences and constraints regarding availability of healthcare services) were found. The results of this study highlight the importance of an integrative approach, raising awareness of the benefits regarding early detection of autism spectrum disorder in preventive care, the need of continuous investment in easy and accessible training and active screening, and a closer collaboration between preventive care organizations and autism spectrum disorder experts.

Contains fulltext : 235396.pdf (Publisher’s version ) (Open Access) In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Contains fulltext : 237708pub.pdf (Publisher’s version ) (Open Access) Contains fulltext : 237708.pdf (Author’s version postprint ) (Open Access) ADHD is a disorder characterized by changes in the reward system and which is highly comorbid with other mental disorders, suggesting common neurobiological pathways. Transdiagnostic neuroimaging findings could help to understand whether a dysregulated reward pathway might be the actual link between ADHD and its comorbidities. We here synthesize ADHD neuroimaging findings on the reward system with findings in obesity, depression, and substance use disorder including their comorbid appearance regarding neuroanatomical features (structural MRI) and activation patterns (resting-state and functional MRI). We focus on findings from monetary-incentive-delay (MID) and delay-discounting (DD) tasks and then review data on striatal connectivity and volumetry. Next, for better understanding of comorbidity in adult ADHD, we discuss these neuroimaging features in ADHD, obesity, depression and substance use disorder and ask whether ADHD heterogeneity and comorbidity are reflected by a common dysregulation in the reward system. Finally, we highlight conceptual issues related to heterogeneous paradigms, different phenotyping, longitudinal prediction and highlight some promising future directions for using striatal reward functioning as a clinical biomarker.

Contains fulltext : 237700.pdf (Publisher’s version ) (Open Access) Pathological aggression is a debilitating feature of many neuropsychiatric disorders, and cingulate cortex is one of the brain areas centrally implicated in its control. Here we explore the specific role of midcingulate cortex (MCC) in the development of pathological aggression. To this end, we investigated the structural and functional degeneration of MCC in the BALB/cJ strain, a mouse model for pathological aggression. Compared to control animals from the BALB/cByJ strain, BALB/cJ mice expressed consistently heightened levels of aggression, as assessed by the resident-intruder test. At the same time, immunohistochemistry demonstrated stark structural degradation in the MCC of aggressive BALB/cJ mice: Decreased neuron density and widespread neuron death were accompanied by increased microglia and astroglia concentrations and reactive astrogliosis. cFos staining indicated that this degradation had functional consequences: MCC activity did not differ between BALB/cJ and BALB/cByJ mice at baseline, but unlike BALB/cByJ mice, BALB/cJ mice failed to activate MCC during resident-intruder encounters. This suggests that structural and functional impairments of MCC, triggered by neuronal degeneration, may be one of the drivers of pathological aggression in mice, highlighting MCC as a potential key area for pathologies of aggression in humans.

Contains fulltext : 234086.pdf (Publisher’s version ) (Closed access) Controlling aggression is a crucial skill in social species like rodents and humans and has been associated with anterior cingulate cortex (ACC). Here, we directly link the failed regulation of aggression in BALB/cJ mice to ACC hypofunction. We first show that ACC in BALB/cJ mice is structurally degraded: neuron density is decreased, with pervasive neuron death and reactive astroglia. Gene-set enrichment analysis suggested that this process is driven by neuronal degeneration, which then triggers toxic astrogliosis. cFos expression across ACC indicated functional consequences: during aggressive encounters, ACC was engaged in control mice, but not BALB/cJ mice. Chemogenetically activating ACC during aggressive encounters drastically suppressed pathological aggression but left species-typical aggression intact. The network effects of our chemogenetic perturbation suggest that this behavioral rescue is mediated by suppression of amygdala and hypothalamus and activation of mediodorsal thalamus. Together, these findings highlight the central role of ACC in curbing pathological aggression. 13 p.

Contains fulltext : 251409.pdf (Publisher’s version ) (Open Access) BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD. METHODS: We obtained diffusion-weighted imaging (DWI) data from 99 participants at two timepoints (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time-points. RESULTS: Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST; P (FWE) = 0.038 and P (FWE) = 0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (P (FWE) = 0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments. CONCLUSIONS: In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.

Mechanisms underpinning age-related variations in cortical thickness in the human brain remain poorly understood. We investigated whether inter-regional age-related variations in cortical thinning (in a multicohort neuroimaging dataset from the ENIGMA Lifespan Working Group totalling 14,248 individuals, aged 4-89 years) depended on cell-specific marker gene expression levels. We found differences amidst early-life (60 years) in the patterns of association between inter-regional profiles of cortical thickness and expression profiles of marker genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated that each of the three life-stages was associated with different biological processes and cellular components: synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights into age-related cortical thinning during typical development and aging.

Although the importance of early detection and early intervention of autism spectrum disorders (ASD) is widely recognized, multiple barriers exist in accessing early intervention services. As an alternative to these barriers, the SCOPE project presents a new, easy accessible and blended intervention called BEAR (Blended E-health for children at eArly Risk). This paper describes this BEAR intervention and study design of an ongoing two arm cluster randomized controlled trial (RCT).BEAR (Blended E-health for children at eArly Risk) is a blended e-health intervention, based on evidence-based naturalistic developmental behavioral interventions (NDBI's) and can be offered to parents and infants/toddlers at high likelihood for ASD. During the ongoing RCT, N = 88 high risk infants and toddlers will be cluster randomized over the BEAR intervention and care-as-usual (CAU) conditions. The finalized version of the intervention protocol and study design are presented in this paper. The primary outcome measure is joint engagement measured by the Joint Engagement Rating Inventory (JERI) during videotaped parent-child interaction. Secondary outcome measures include severity of ASD symptoms, global level of adaptive functioning, parental well-being, parental skills and satisfaction with healthcare. Also, costs will be estimated from society's perspective. Assessments take place at the start of the study (T1), after eight weeks (T2) and after six months (T3) and include behavioral home observations and parental questionnaires.The SCOPE project aims to contribute to improved early identification and timely start of suitable interventions for infants and toddlers at elevated likelihood for ASD. This ongoing RCT will offer insight in the feasibility, short-term and six months effects of the innovative BEAR intervention. It is estimated that inclusion for the trial (N = 88) is completed in spring 2023.Dutch Trial Register, NTR7695. Registered at December 17

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder and is associated with structural grey matter differences in the brain. We investigated the genetic background of some of these brain differences in a sample of 899 adults and adolescents consisting of individuals with ADHD and healthy controls. Previous work in an overlapping sample identified three ADHD-related grey matter brain networks located in areas of the superior, middle, and inferior frontal gyrus as well as the cerebellar tonsil and culmen. We associated these brain networks with protein coding genes using a statistical stability selection approach. We identified ten genes, the most promising of which were NR3C2, TRHDE, SCFD1, GNAO1, and UNC5D. These genes are expressed in brain and linked to neuropsychiatric disorders including ADHD. With our results we aid in the growing understanding of the aetiology of ADHD from genes to brain to behaviour.

Contains fulltext : 288245.pdf (Publisher’s version ) (Open Access) BACKGROUND: The cerebellum contains more than 50% of the brain's neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism. METHODS: We studied cerebellar gray matter morphology in 274 individuals with autism and 219 control subjects of a multicenter European cohort, EU-AIMS LEAP (European Autism Interventions-A Multicentre Study for Developing New Medications; Longitudinal European Autism Project). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with 2 different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate (including normative modeling), and meta-analytic approaches to capture the diversity of cerebellar anatomy in individuals with autism and control subjects. Finally, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms. RESULTS: We did not find any significant difference in the cerebellum when comparing individuals with autism and control subjects using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related to age, IQ, sex, or social functioning in individuals with autism. CONCLUSIONS: Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism.

BACKGROUND: Dietary patterns have been associated with variations in behavior. However, evidence has been limited and mixed, and the underlying mechanism remains unclear.OBJECTIVE: Extend a previous study reporting significant associations between food patterns and behavioral disinhibition and explore whether low-grade inflammation is linked to behaviors and mediates the association between diet and behavioral disinhibition.DESIGN: Among participants of the UK Biobank (UKB) we extracted a single behavioral disinhibition principal component using the UKB touchscreen questionnaire, Mental Health Questionnaire (MHQ), and registered diagnoses. We identified four dietary patterns (prudent diet, elimination of wheat/dairy/eggs, meat-based diet, full-cream dairy consumption) by using the Food Frequency Questionnaire (FFQ). Immune biomarkers and an aggregated inflammation score (INFLA-score) were used to characterize low-grade inflammation. Associations between dietary patterns and immune biomarkers, between immune biomarkers and disinhibition were assessed, with adjustment for demographics, lifestyle factors, and somatic health conditions. Next, mediation analyses were run to examine whether the association between dietary patterns and disinhibition was partially explained by inflammatory levels. We also conducted subgroup analyses to explore whether associations and the mediation effect differed by sex, age, ethnicity/race, body-mass-index (BMI), and socioeconomic status (SES).RESULTS: The prudent diet was negatively, and the meat-based diet was positively associated with several pro-inflammatory biomarkers. Most immune biomarkers were positively associated with disinhibition (numbers of lymphocytes (βstandardized = 0.082, p < 0.001), monocytes (βstandardized = 0.043, p < 0.001), neutrophils (βstandardized = 0.071, p < 0.001), platelets (βstandardized = 0.022, p < 0.001), leukocytes (βstandardized = 0.093, p < 0.001), C-reactive protein (βstandardized = 0.051, p < 0.001), and for INFLA-score (βstandardized = 0.074, p < 0.001). In the mediation model, the INFLA-score mediated the association between prudent diet and meat-based diet and disinhibition score, with a significant indirect effect of low-grade inflammation for the prudent diet-disinhibition association (βstandardized = -0.007, p < 0.001) and for meat-disinhibition association (βstandardized = 0.001, p < 0.001)). Although all effects were small, covariates and interaction term adjustments did not attenuate the effects, and neither did most subgroup-only analyses.CONCLUSIONS: The prudent diet was associated with a lower disinhibition score and this effect was partially mediated by the lower inflammation. Reversely, the meat-based diet was linked to more inflammation, which was associated with more disinhibition. Our findings suggest mediating effects of immune function in the relationship between diet and behavioral disinhibition. However further alternative designs such as interventional trials are needed to establish causal effects.

Little is known about factors contributing to perceived stigma in parents of children and adolescents with behavioral and emotional problems in outpatient mental healthcare. We aimed to identify the most relevant factors related to perceived parental stigma using least absolute shrinkage and selection operator (LASSO) regression including a broad range of factors across six domains: (1) child characteristics, (2) characteristics of the primary parent, (3) parenting and family characteristics, (4) treatment-related characteristics, (5) sociodemographic characteristics, and (6) social–environmental characteristics. We adapted the Parents’ Perceived Stigma of Service Seeking scale to measure perceived public stigma and affiliate stigma in 312 parents (87.8% mothers) during the first treatment year after referral to an outpatient child and adolescent clinic. We found that the six domains, including 45 individual factors, explained 34.0% of perceived public stigma and 19.7% of affiliate stigma. Child and social–environmental characteristics (social relations) explained the most deviance in public stigma, followed by parental factors. The strongest factors were more severe problems of the child (especially callous–unemotional traits and internalizing problems), mental healthcare use of the parent, and lower perceived parenting competence. The only relevant factor for affiliate stigma was lower perceived parenting competence. Our study points to the multifactorial nature of perceived stigma and supports that parents’ perceived public stigma is susceptible to social influences, while affiliate stigma relates to parents’ self-evaluation. Increasing parents’ perceived parenting competence may help mitigate perceived stigma. Future studies should explore how stigma relates to treatment outcomes.

The clinical heterogeneity of autism spectrum disorders majorly challenges their genetic study. Autism spectrum disorders symptoms occur in milder forms in the general population, as autistic-like traits, and share genetic factors with autism spectrum disorders. Here, we investigate the genetics of individual autistic-like traits to improve our understanding of autism spectrum disorders. We meta-analysed four population-based genome-wide association studies investigating four autistic-like traits – ‘attention-to-detail’, ‘imagination’, ‘rigidity’ and ‘social-skills’ ( n = 4600). Using autism spectrum disorder summary statistics from the Psychiatric Genomic Consortium ( N = 46,350), we applied polygenic risk score analyses to understand the genetic relationship between autism spectrum disorders and autistic-like traits. Using MAGMA, we performed gene-based and gene co-expression network analyses to delineate involved genes and pathways. We identified two novel genome-wide significant loci – rs6125844 and rs3731197 – associated with ‘attention-to-detail’. We demonstrated shared genetic aetiology between autism spectrum disorders and ‘rigidity’. Analysing top variants and genes, we demonstrated a role of the immune-related genes RNF114, CDKN2A, KAZN, SPATA2 and ZNF816A in autistic-like traits. Brain-based genetic expression analyses further linked autistic-like traits to genes involved in immune functioning, and neuronal and synaptic signalling. Overall, our findings highlight the potential of the autistic-like trait–based approach to address the challenges of genetic research in autism spectrum disorders. We provide novel insights showing a potential role of the immune system in specific autism spectrum disorder dimensions. Lay abstract Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients.

The excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between glutamatergic and GABAergic neurotransmission contributes to autism symptomatology. Whether this is due to altered GABAergic or glutamatergic functioning, or both, remains largely unknown. We integrated genetic, brain structure and brain chemistry data to investigate the relationship between E/I genetic variation and expression, glutamate concentrations and cortical thickness (CT). Participants (60 autism and 104 neurotypical controls, aged 8-13 years) underwent magnetic resonance imaging and spectroscopy for glutamate quantification in the anterior cingulate cortex (ACC) and left dorsal striatum. Genetic involvement in these regional glutamate concentration levels was investigated using competitive gene-set association and polygenic scores (PGS). Further, glutamate as well as GABA gene-set expression profiles were investigated in relation to CT. Aggregated genetic variation in the glutamate gene-set was associated with ACC but not striatal glutamate concentrations. PGS analysis, however, showed a genome-wide PGS for autism to be predictive of striatal but not ACC glutamate levels. Expression profiles of GABAergic-but not glutamatergic genes were associated with differences in cortical thickness between groups. This study showed differential involvement of aggregated glutamatergic and GABAergic genetic variation in brain structure and chemistry in autism, which suggests regional variability in E/I imbalance.

Contains fulltext : 282637.pdf (Publisher’s version ) (Closed access) Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by difficulties in social communication, but also great heterogeneity. To offer individualized medicine approaches, we need to better target interventions by stratifying autistic people into subgroups with different biological profiles and/or prognoses. We sought to validate neural responses to faces as a potential stratification factor in ASD by measuring neural (electroencephalography) responses to faces (critical in social interaction) in N = 436 children and adults with and without ASD. The speed of early-stage face processing (N170 latency) was on average slower in ASD than in age-matched controls. In addition, N170 latency was associated with responses to faces in the fusiform gyrus, measured with functional magnetic resonance imaging, and polygenic scores for ASD. Within the ASD group, N170 latency predicted change in adaptive socialization skills over an 18-month follow-up period; data-driven clustering identified a subgroup with slower brain responses and poor social prognosis. Use of a distributional data-driven cutoff was associated with predicted improvements of power in simulated clinical trials targeting social functioning. Together, the data provide converging evidence for the utility of the N170 as a stratification factor to identify biologically and prognostically defined subgroups in ASD.

Contains fulltext : 234343.pdf (Publisher’s version ) (Open Access) Patients with attention-deficit/hyperactivity disorder (ADHD) are often diagnosed with comorbid substance misuse (SM), which is associated with poor treatment efficacy. Although literature indicates similar inhibitory control deficits in both conditions, it is unclear whether SM in ADHD exaggerates pre-existing deficits, with additive or distinct impairments in patients. Our aim was to examine SM effects on inhibitory control in ADHD. Behavioural and functional magnetic resonance imaging (fMRI) data from a stop-signal task were compared across ADHD patients with and without SM (ADHD + SM and ADHD-only, respectively) and controls (n = 33/group; 79 males, mean age 18.02 ± 2.45). To limit substance use disorder (SUD) trait effects, groups were matched for parental SUD. Overall, we found worse performance for ADHD-only and/or ADHD + SM compared with controls but no difference between the ADHD groups. Moreover, the ADHD groups showed decreased frontostriatal and frontoparietal activity during successful and failed stop trials. There were no differences between the ADHD groups in superior frontal nodes, but there was more decreased activation in temporal/parietal nodes in ADHD-only compared with ADHD + SM. During go-trials, ADHD + SM showed decreased activation in inferior frontal nodes compared with ADHD-only and controls. Findings during response inhibition showed deficits in inhibition and attentional processes for ADHD patients with and without SM. Despite no evidence for SM effects during response inhibition, results during go-trials suggest distinct effects on nodes that are associated with several executive functions. Future studies should investigate whether distinct deficits in ADHD + SM relate to poor treatment results and can direct development of distinct ADHD treatment strategies for these patients. 11 p.

Pivotal Response Treatment (PRT) is a promising intervention addressing core symptoms of autism spectrum disorder (ASD), with parent involvement as key component. Parent group-delivered PRT may be an effective treatment model, but currently the evidence is limited. Also, little attention has been paid to therapeutic involvement of multiple important contexts (e.g. home, school, community) of the young child. The current study explores a 14-week protocol of PRT parent group training (PRT-PG), complemented with individual parent–child sessions and involvement of teachers and other childcare providers. Children aged 2–6 years old with ASD and their parents (n = 20) were included. Preliminary results showed a significant increase in spontaneous initiations during a semi-structured therapist-child interaction together with widespread gains in clinical global functioning. No significant improvement on parent-rated general social-communication skills was observed. These findings justify further research on parent group delivered PRT models.

Major depressive disorder is a severe illness that frequently manifests before the age of 18 years, often recurring later in life. Paediatric medical treatment options are scarce. The melatonin receptor agonist and 5-hydroxytryptamineWe performed a 12 week, randomised, double-blind, parallel-group, multicentre, phase 3 trial in 46 specialist psychiatric units or centres in Bulgaria, Finland, Hungary, Poland, Romania, Russia, Serbia, South Africa, and Ukraine. Participants (aged 7-17 years) were eligible if they were unresponsive to psychosocial therapy during the 3-week run-in period (Children's Depression Rating Scale-revised [CDRS-R] score of ≥45). Ethnicity was not recorded. We investigated short-term antidepressant efficacy of agomelatine (10 mg or 25 mg per day) versus placebo with an active control (fluoxetine 10-20 mg depending on symptom severity) after 12 weeks of treatment in children (aged 7-11 years) and adolescents (12-17 years) with major depressive disorder. Patients were randomly assigned (1:1:1:1) to agomelatine 10 mg, agomelatine 25 mg, placebo, or fluoxetine via an interactive response system with permuted-block randomisation. Standardised manualised psychosocial counselling, developed for this trial, was initiated from selection and continued throughout the study, including the open-label extension. All people involved in the conduct of the clinical trial and patients were masked to treatment allocation. Study outcomes were measured using standardised interviews at each study visit. The primary endpoint was change in CDRS-R raw score from baseline to week 12. This study is registered with EudraCT, 2015-002181-23.Between Feb 23, 2016, and Jan 14, 2020, 466 individuals were assessed for eligibility and of 400 included patients, 396 (247 [62%] girls, 149 [38%] boys; mean age 13·7 years [SD 2·7]) were analysed (full analysis set). The primary objective was met; 25 mg/day agomelatine (n=94, with n=102 receiving 10 mg/day) resulted in an improvement versus placebo (n=101) in CDRS-R raw score of 4·22 (95% CI 0·63-7·82; p=0·040) at 12 weeks, with a similar effect for fluoxetine (n=99), establishing assay sensitivity. The overall effect was confirmed in adolescents (n=317), but not in children (n=79). No unexpected safety signals were observed with agomelatine, with no significant weight gain or effect on suicidal behaviours.This first study in a paediatric population supports the efficacy of 25 mg/day agomelatine, in addition to psychosocial counselling, in treating adolescent patients with major depressive disorder, with no unexpected safety signals. This medication could provide another option in the limited psychopharmaceutical repertoire for management of major depressive disorder.Servier. VIDEO ABSTRACT.

Contains fulltext : 246486.pdf (Publisher’s version ) (Open Access) Whereas it is well documented how parents experience the diagnostic process of their child with autism spectrum disorder (ASD), less is known about parental experiences with the course of the early identification process and first steps in receiving care for their child with ASD symptoms. This mixed-method study investigated these experiences as well as barriers and improvement strategies regarding early detection in the Netherlands. A parental survey (N = 45) showed that, on average, initial concerns started at 22 months. A focus group (N = 10) revealed multiple barriers and proposed strategies of improvement in three domains: "Knowledge and Expertise", "Attention to Parental Needs" and "System and Organization". Strategies to improve early identification will be discussed based on parental perspectives and professional perspectives. 13 p.

Background. Dietary habits may influence chronic low-grade inflammation in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. Methods. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of the 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation (NPEM) was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. Results. We identified 3 dietary patterns, characterized as “high-meat” (meat and sweetened drink), “prudent diet” (fish, fruit, legumes and vegetables) and “high alcohol” (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. Conclusion. A meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. Our study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.

BackgroundThe excitatory/inhibitory (E/I) imbalance hypothesis posits that an imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism spectrum disorder (autism). However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood.MethodsWe used innovative analysis methods - combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT)- to investigate the relationship between genetic variance, brain structure and autism symptomatology of participants from the EU-AIMS LEAP cohort (autism=360, male/female=259/101; neurotypical control participants=279, male/female=178/101) aged 6 to 30 years. Competitive gene-set analysis investigated associations between glutamatergic and GABAergic signaling pathway gene-sets and clinical measures, and CT. Additionally, we investigated expression profiles of the genes within those sets throughout the brain and how those profiles relate to differences in CT between autistic and neurotypical control participants in the same regions.ResultsThe glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group, while the GABA set was associated with sensory processing measures (using the SSP subscales) across all participants. Brain regions with greater gene expression of both glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants.ConclusionsOur results suggest crucial roles for glutamate and GABA genes in autism symptomatology as well as CT, where GABA is more strongly associated with sensory processing and glutamate more with autism symptom severity.

Contains fulltext : 251347.pdf (Publisher’s version ) (Open Access) While pharmacological treatment with methylphenidate (MPH) is a first line intervention for ADHD, its mechanisms of action have yet to be elucidated. We here seek to identify the white matter tracts that mediate MPH's effect on beta oscillations. We implemented a double-blind placebo-controlled crossover design, where boys diagnosed with ADHD underwent behavioral and MEG measurements during a spatial attention task while on and off MPH. The results were compared with an age/IQ-matched control group. Estimates of white matter tracts were obtained using diffusion tensor imaging (DTI). Via a stepwise model selection strategy, we identified the fiber tracts (regressors) significantly predicting values of the dependent variables of interest (i.e., oscillatory power, behavioral performance, and clinical symptoms): the anterior thalamic radiation (ATR), the superior longitudinal fasciculus ("parietal endings") (SLFp), and superior longitudinal fasciculus ("temporal endings") (SLFt). ADHD symptoms severity was associated with lower fractional anisotropy (FA) within the ATR. In addition, individuals with relatively higher FA in SLFp compared to SLFt, led to stronger behavioral effects of MPH in the form of faster and more accurate responses. Furthermore, the same parietotemporal FA gradient explained the effects of MPH on beta modulation: subjects with ADHD exhibiting higher FA in SLFp compared to SLFt also displayed greater effects of MPH on beta power during response preparation. Our data suggest that the behavioral deficits and aberrant oscillatory modulations observed in ADHD depend on a possibly detrimental structural connectivity imbalance within the SLF, caused by a diffusivity gradient in favor of parietal rather than temporal, fiber tracts.